1. Field of the Invention
The invention relates to methods of treating multiple sclerosis.
2. Description of the Prior Art
Multiple sclerosis is a disorder of the central nervous system white matter characterized by local areas of inflammation, demyelination and gliosis. It is characterized by episodes of disorders of the optic nerves, spinal cord and brain which remit and recur over many years. This disease has a prevalence of 80 per 100,000 in Canada, Europe and the northern United States. Most cases have their onset in which individuals between 20 and 40 years of age. Most patients are eventually disabled by progressive paraplegia and/or ataxia.
Possible etiologies for multiple sclerosis include autoimmunity, viruses, free radical formation, mast cell mediation and the undecapeptide substance P which mediates augmented vascular permeability and vasodilation, possibly in a mast-cell dependent fashion. See J. E. Merrill et al., J. Clin. Immun., 9: 84-89 (1989); M. Rodriguez, Mayo Clin. Proc., 64: 570-576 (1989); E. Orr, Ann. New York Acad. Sci., 1989, 723-726; S. K. Kostyk et al., Brain Res., 504: 284-288 (1989).
Studies suggest that mast cells participate in the pathophysiology of multiple sclerosis (Y. Olsson et al., Acta Neurol. Scandinav., 50: 611-618 (1974)). The brain mast cells release vasoactive amines which may cause demyelination (D. Johnson et al., Ann. New York Acad. Sci., 1989, 727-728). Also, these brain mast cells are in close proximity to peptidergic neurons which secrete neurotensin and substance P (C.M.S. Fewtrell et al., J. Physiol., 330: 393-411 (1982)). Substance P not only is a potent mast cell stimulator but recently has been strongly implicated in the pathogenesis of multiple sclerosis plaques (S. K. Kostyk et al., supra). Histamine released from mast cells may alter blood vessel integrity and cause partial breakdown of the blood-brain barrier again implicated in the etiology of multiple sclerosis (W. I. Rosenblum, Brain Res., 49: 75-82 (1973)). In addition, viral infection has been linked to multiple sclerosis and mast cells secrete with viral stimulation (K. Sugiyama, Nature, 370: 614-615 (1977)).
Nalmefene (6-methylene-6-desoxy-N-cyclopropylmethyl-14-hydroxydihydronormorphine) is a long-acting, orally available, potent narcotic antagonist with pure antagonist activity. Apart from its utility in antagonizing the sedation, respiratory depression and other actions of opioid agents, nalmefene has also been found useful in treating diverse conditions such as hyperkinesia in children (U.S. Pat. No. 4,454,142), senile dementia (U.S. Pat. No. 4,511,570), sudden infant death syndrome (U.S. Pat. No. 4,639,455), autoimmune diseases (U.S. Pat. No. 4,857,533), arthritic and inflammatory diseases (U.S. Pat. No. 4,863,928), interstitial cystitis (U.S. Pat. No. 4,877,791), allergic rhinitis (U.S. Pat. No. 4,880,813) and mast cell-mediated dermatological disorders (U.S. Pat. No. 4,923,875).
Naltrexone (N-cyclopropylmethyl-14-hydroxydihydromorphinone) is another orally available narcotic antagonist with pure antagonist activity. Naltrexone has additionally been disclosed as useful for inducing anorexia (U.S. Pat. Nos. 4,477,457; 4,478,840) and for treating shock (U.S. Pat Nos. 4,267,182; 4,434,168).
In U.S. Pat. Nos. 4,877,791 and 4,923,875 it is disclosed that pure narcotic antagonists such as nalmefene and naltrexone may suppress histamine release from mast cells found in the bladder walls and the skin. Pure narcotic antagonists have not, however, been heretofore disclosed as having any utility in the treatment of multiple sclerosis or other neurodegenerative disorders.
There does not currently exist any modality of drug treatement for multiple sclerosis known to be safe and effective in a significant number of cases.